O-GlcNAc transferase regulates intervertebral disc degeneration by targeting FAM134B-mediated ER-phagy

Both O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention. Back pain: Preserving the spine's padding A cellular 'housekeeping' mechanism that counters the detrimental effects of stress could also help protect against lower back pain by preventing degeneration of the spongy discs that cushion our vertebrae. When subjected to traumatic conditions such as nutrient deprivation, some cells respond by breaking down excess components of an intracellular organelle, the endoplasmic reticulum (ER). Researchers led by Yu Song and Cao Yang at Huazhong University of Science and Technology, Wuhan, China, have shown that this 'ER-phagy' response helps promote the survival of stressed nucleus pulposus (NP) cells, the inner core of intravertebral discs. Cultured human NP cells tend to die off in starvation conditions, but were sustained by activation of ER-phagy pathways. This same mechanism was shown to prevent disc degeneration in rats, suggesting a potential therapeutic strategy for preventing lower back pain in humans.

Automated summary

O-GlcNAcylation and ER-phagy are adaptive regulatory mechanisms that play important roles in various diseases. This study reveals that O-GlcNAcylation and ER-phagy are involved in intervertebral disc degeneration, and they help maintain cellular homeostasis by enhancing cell function and survival.